Pancreastatin inhibitor activates AMPK pathway via GRP78 and ameliorates dexamethasone induced fatty liver disease in C57BL/6 mice

Biomed Pharmacother. 2019 Aug;116:108959. doi: 10.1016/j.biopha.2019.108959. Epub 2019 May 17.

Abstract

Aims: To investigate the role of pancreastatin inhibitor (PSTi8) in lipid homeostasis and insulin sensitivity in dexamethasone induced fatty liver disease associated type 2 diabetes.

Main methods: Glucose releases assay, lipid O staining and ATP/AMP ratio were performed in HepG2 cells. Twenty four mice were randomly divided into 4 groups: Control group (saline), DEX (1 mg/kg, im) for 17 days, DEX+PSTi8 (acute 5 mg/kg and chronic 2 mg/kg, ip) for 10 days. The glucose, insulin and pyruvate tolerance tests (GTT, ITT and PTT), biochemical parameters and Oxymax-CLAMS were performed. Further to elucidate the action mechanisms of PSTi8, we performed genes expression and western blotting of biological samples.

Key findings: We found that PSTi8 suppresses hepatic glucose release, lipid deposition, oxidative stress induced by DEX, stimulates the cellular energy level in hepatocytes and enhances GRP78 activity. It reduces lipogensis and enhances fatty acid oxidation to improve insulin sensitivity and glucose tolerance in DEX induced diabetic mice. The above cellular effects are the result of activated AMPK signalling pathway in liver, which increases Srebp1c and ACC phosphorylation. The increased ACC phosphorylation suppresses protein kinase C activity and enhances insulin sensitivity. The increased expression of UCP3 in liver elicits fatty acid oxidation and energy expenditure, which suppress oxidative stress.

Significance: Thus the activation of AMPK signalling through GRP78, improves lipid homeostasis, enhances insulin sensitivity via inhibition of PKC activity. PSTi8 suppresses inflammation associated with incomplete fatty acid oxidation. Hence, PSTi8 may be a potential therapeutic agent to treat glucocorticoid-induced fatty liver associated type 2 diabetes.

Keywords: Dexamethasone; Diabetes; Fatty liver disease; GRP78; Insulin resistance; PSTi8; Pancreastatin.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Triphosphate / metabolism
  • Adipokines / metabolism
  • Adiposity / drug effects
  • Animals
  • Chromogranin A / antagonists & inhibitors*
  • Chromogranin A / metabolism
  • Dexamethasone
  • Energy Metabolism
  • Fatty Liver / blood
  • Fatty Liver / enzymology*
  • Fatty Liver / pathology*
  • Glucose / metabolism
  • Heat-Shock Proteins / metabolism*
  • Hep G2 Cells
  • Homeostasis / drug effects
  • Humans
  • Insulin / blood
  • Insulin Resistance
  • Lipid Metabolism / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Inbred C57BL
  • Signal Transduction*
  • Tissue Distribution / drug effects

Substances

  • Adipokines
  • Chromogranin A
  • Heat-Shock Proteins
  • Insulin
  • pancreastatin
  • Dexamethasone
  • Adenosine Triphosphate
  • AMP-Activated Protein Kinases
  • Glucose
  • molecular chaperone GRP78